The meeting. Joining us this afternoon or morning, depending on where you are. We are going to get started here with Edgewise in a few seconds. We're just gonna let more attendees trickle in, and then Pat will get us kicked off. All right, Pat. It looks like our numbers are starting to level out a little bit. If you wanna get us started. Thanks, Emily. Welcome, everyone. Good morning, good afternoon, where you live. We're really thrilled to have you today, and today we're lucky enough to be talking about sevasemten. I'm gonna have to get practice on how to pronounce this, Joanne and Abby, and really talking about the Canyon trial. We are thrilled to have Abby Bronson, who's the Vice President of Patient Advocacy and External Innovation, and Joanne Donovan, their Edgewise Chief Medical Officer. So with that, we're gonna get started, and Abby, I'll turn this over to you. Thank you, Pat, and thanks to PPMD for organizing this opportunity for us to talk about sevasemten is how you say it. Sometimes we refer to it as seva. The top-line results from our Canyon phase 2 trial in Becker. Now the slide is not advancing. When we did it before, we just had a run-through and it worked, and now it is not working. Why is that? Sometimes if you click in the slide and then hit the advance, it works. That works. Okay. So here. Thank you, Joanne. So here's our forward-looking statement. I think the most important part to know is that Sevasemten is not approved in any country, territory, anywhere. We'll be talking about things in the future. Joanne and I are both employees of Edgewise, which is a public company. So I just wanna go over what you're gonna hear about today. So a little bit on who is Edgewise. We'll talk a little bit about how muscles are damaged in Becker. This is all background for really understanding the trial results. What is the Edgewise approach, and how do we measure progression in Becker? Because again, these are really important to understand for when we talk about the trial results. Then we'll have a little some information on next steps and then the Q&A. So who is Edgewise? We are a company that was founded in 2017. We're very focused on muscle biology and muscle disease therapeutic development. We started out focusing our efforts on developing novel muscle-targeted therapies for the muscular dystrophies, and specifically on contraction-induced muscle injury in Becker and Duchenne and how do we protect that muscle during those contractions. As you know, we have an investigational agent, sevasemten. Our hope is that it will be a daily oral pill and that it will be able to be used alone or in combination with other therapies. I think our whole company, since our inception, has been very mission-driven. We have a lot of patient focus and are very equally involved in serving the community that we work in as well as developing drugs in them. This is a little I put this in just a little, so I could talk about the commitment and some of the ways that we have invested in educating and building the Becker community. We've done a lot of qualitative interviews and receiving information back from Becker, trying to understand the lived experience of Becker through focus groups. We have a Becker Patient Council. We have done a lot of one-on-one interviews, quantitative surveys. We've developed the Becker Conceptual Model, which describes the symptoms that are most important to Becker patients. This all helps us inform our drug development program, just makes us do whatever we do better. We've developed a lot of educational resources for the Becker community. We have a Becker Muscular Dystrophy disease website. We supported a TREAT-NMD masterclass for clinicians on Becker Muscular Dystrophy. We've had a lot of these types of educational webinars with PPMD and some of the other organizations. And we're working on standards of care along with all our partners. We've also done a lot of community building in the Becker space. I don't know if many of you have heard of BEAD, but we were part of the steering committee who started this a couple of years ago. And it's really grown in the two years that we've been part of it and has really served to build community, give Becker patients a place to connect and share their experiences and learn about the standards of care and the current research therapy. So we've really learned a lot and given a lot to the community. And I think it's all paying off. So again, this is just a little review for most of you because I think it's important when we talk about the results of the trial. So how are muscles damaged in Becker and what is our approach? So this little graphic is just a schematic that shows you how healthy muscles contract and then those muscles that are dystrophic, meaning they have a complete absence of or only partial dystrophin. So the fibers on the left-hand side, you can see how they're all connected by those little blue things. And that's supposed to represent the dystrophin. And when it contracts, you can see that the fibers are contracted. If the fiber in the middle is contracting and all the other ones, because they're connected, they're kind of moving with it. But they're all connected so that one fiber is not taking the whole force of the contraction. Without dystrophin, if you look on the right-hand side, you don't have those fibers connected. So when that middle one, that one fiber is connecting, it takes all the mechanical stress of the contraction. And that's where the fiber starts to break down, the membrane starts to get very weak, and they start to develop leaks. And so that is, that's the contraction-induced injury, what we're trying to protect. And the other thing is that it is the type II fibers we learned that are the ones that are most susceptible to this type of injury. And that's an important part of our approach as well. Our approach is that, again, based on that schematic and knowing that it's the type II fibers that are breaking down more first, we took that knowledge and we decided to make a sevasemten or an investigational therapy that protects these susceptible muscle fibers from damage regardless of the mutation. We're directly targeting those fibers. When we did our pre-clinical work before we went into humans and diseased animal models, the sevasemten protected the susceptible, those type II skeletal muscle fibers. And also long-term, we saw that there was a prevention of that contraction-induced damage. An initial clinical trial in Becker, this is the ARCH trial, sevasemten showed a decrease in biomarkers of muscle damage and also showed trends towards functional improvement in comparison to the natural history. We had some initial data. So how do we measure progression in Becker? So the schematic on the left is just a kind of a different view of the schematic I showed earlier. It's when during contraction, there's excessive degeneration. And when that muscle fiber starts to experience that stress, those little leaks, those holes are formed. The fast fibers are subsequently injured and they release the muscle injury biomarkers into circulation. So these muscle injury biomarkers, and you can see, CK is one that we'll be talking about and TNNI2, which is a biomarker that is specifically related to fast muscle fibers. We use those to, they can be measured to determine ongoing muscle damage and muscular dystrophy. So those are the biomarkers that we'll be talking about in the results. The North Star wasn't the primary outcome of the trial, but it was the functional measure that we used to look at, or one of them, function, and just as a reminder, it includes 17 different activities such as rising from a chair, walking, standing, jumping, hopping, going up and down. It is used to measure function in those who are able to walk. Each activity is scored on zero, which means you can't do the item at all. One, you can do it, but with an adaptation because you have some weakness. Or two, and that means that you have no adaptations at all. The best score if someone did everything well would be 34. If you couldn't do anything, it would be zero. It's used in a lot of Duchenne trials. It's a very well-established and standardized tool, and that's what we'll be talking about the North Star as well, so there are some natural history studies just looking at the disease progression, and they have used North Star as the measure to see what the disease is doing, so in Becker, the disease, it will progress over the lifespan, patients will progress at different times, sometimes it's related to age of diagnosis, just severity of disease, and they may not experience weakness or progression in a consistent order, and then once individuals living with Becker have started to experience loss of muscle function, that decrease will continue and it will be a persistent decline. So if you think about the North Star and what we just talked about, that scale from zero to 34 and those 17 items, so even if you have a North Star changing from like 20 to 19 or 20 to 18, it seems like, well, out of a scale of 34, that's not very much. But over a two-year period of time for a Becker patient, that could look like, you know, you could be able to use the toilet independently and then you could lose that function and you'd have to ask for help to get up. Or going up, you know, go navigating stairs or step over a side sidewalk, that could be another thing that could be affected just in two years by a North Star score of one or two. being able to get up from a fall, it could require someone else's help to get back up. So those are the, you know, I'm just pointing this out because I think that these are all items that are very, very meaningful to patients. And these are the types of things that we are trying to prevent. So with that, I'm gonna turn it over to Joanne, who's gonna go over the Canyon top-line results. Thanks, Abby. And thank you, Pat and PPMD, for allowing us to present. We feel it's really important to share the results as soon as possible with the community. And we are really pleased to be able to share these with you today. So to start, what did we do in this study? Of course, on the next slide, the Canyon study built on the previous studies. And Abby, we need to the next slide. We had started with the Arch study, which was an open-label study of two years in individuals with Becker that showed stability of North Star over that time period. And that led to the Canyon study, which in turn has led to the Grand Canyon study, which is a pivotal cohort in adults with Becker muscular dystrophy. We also have an extension study, an open-label extension that includes people who have completed the Arch study, the Canyon study, and the Grand Canyon cohort as well in the Dune. So we are, that is, continuing to understand the longer-term effects of sevasemten in an open-label fashion. And we're looking at safety, biomarkers, and functional measures there. So what did we do in the Canyon study? This was a phase 2 study. So the next step in development after the early phase 1 studies, at many centers, 16 centers, to look at sevasemten, to look at safety, and to look at effect on biomarkers in adults and adolescents with Becker. It wasn't intended to look at functional measures in a well-powered way, in other words, to be a pivotal study. The primary efficacy endpoint, so what we call when we meet the primary endpoint, was looking at the change in CK. Because CK is something that moves up and down, what we decided to do was to look at the average over six, nine, and 12 months. Because what we want to do with this drug? We want to protect the muscles over time. We want to see the effect on biomarkers that could lead us to believe that we are protecting the muscle. Those, the leaky membrane is diminished, and the muscle is protected. That's what we think that the CK and other muscle biomarkers are doing. We wanted to see it over time. We included males aged 12 to 50 who had a dystrophin mutation and a Becker phenotype so that in terms of their disease course, not on corticosteroids. Most Becker patients are not on corticosteroids, and with a North Star at the beginning that was between five and 32, so they were ambulatory, but they were not at the top of the North Star scale, and what we've learned from the natural history is that those who are at the top of the scale, there's something called a ceiling effect. If you're at the top, you may be a little bit above that if the scale was bigger, but you can't see changes there. So if you look at the more the middle of the scale, you're more able to see changes, and so we wanted to understand what the effect was in folks with a North Star between five and 32. We enrolled 40 adults and 29 adolescents between 12 and 17, and the adults, this was a 12-month study. The adults, we initially started with a dose of 10 or 15, and when we realized in Arch that 10 milligrams was the dose, everybody moved to the 10 milligram dose, and there were three patients enrolled on sevasemten versus one on placebo. The adolescents, we were looking to try to understand what would be the appropriate dose for adolescents. They're smaller. They have relatively more muscle tissue, and the drug is very highly concentrated in muscle tissue, so it can affect how the drug is metabolized, so we looked at two different doses, and this was really to understand safety and pharmacokinetics so we could select the dose for the adolescents. We also looked at these functional measures, along the way at several visits, and the patients had visits every three months after the first three months. So on the next slide, the primary endpoint, as I said, was CK. The study was done in three countries, 16 sites. This is the largest interventional Becker study to date. And we're proud of having conducted that. 80 patients were screened for the study and 69 enrolled. Only 4% discontinued during the study, one of the adults out of the 40 enrolled. And it is important to note that of the patients who've been eligible from the Arch study, from the Dune study, and now from the Canyon study, 99% of them have enrolled in the Mesa open-label extension. And that's really important when we look at how do we develop a drug. Because the regulatory authorities also wanna see longer-term. And they wanna see what happens over time in terms of safety, in terms of PK, how the drug is metabolized, and also functional measures. That's a really important part of the study as well. What we saw for the CK is we saw a statistically significant decrease in CK, 28% reduction versus placebo. Now, you know that CK is a very variable measure and that people aren't; docs don't follow that because it doesn't help. It can bounce around in an individual patient. What we saw in the group that was treated with sevasemten, we saw it go down at one month and we saw it stay down. It was pretty reproducible. Those error bars give you a good idea of what the variability in the drug was at three months, six months, nine months, and 12 months. Now you look at the placebo group, those error bars are much larger. You're all looking, well, what's going on there at 12 months? And when you have a group of, in this case, 12 patients with, on placebo, you can see variation in the CK. And that's why we planned, it was pre-specified, to look at the average between six and 12 months. And there we saw the difference on the right between the placebo and the sevasemten group. So we saw that there were rapid and sustained decreases in sevasemten treatment over that period. We also looked at TNNI2, which is another marker of muscle damage. And it's specific to the fast muscle fibers, which, as Abby mentioned, are the ones that get injured first in dystrophinopathies. And TNNI2 decreased 77% from baseline. It again went down rapidly at one month and it stayed down over 12 months. Again, you see it's very tight. Those error bars are small on the symbols for sevasemten over the 12-month period. Placebo, very wide bars there showing there's a lot of variability in placebo, but on average, it doesn't change much. And there's also natural history data now that we had presented actually at World Muscle that that CK is stable over a year. It's variable individually, but the average of a larger group of patients is stable for both CK and TNNI2 with minor decreases over that time. So again, we hit the primary endpoint there, the secondary endpoint. North Star, again, we're not powered to look at this. What we saw was, as we had seen in Arch, that the 28 patients on sevasemten, the blue symbols indicate their North Star, the change from the beginning of the North Star over time. And there's a little wiggling up and down, but basically they're flat. And so that we don't see that there is a decrease over time, which was actually very similar to what we saw in the two years of the ARCH study in a smaller group of patients. We saw that the placebo group went down, approximately the same as the natural history data would indicate. So about one point, a little over one point per year. Natural history is somewhere between one and 1.8 points per year. And as Abby said, that's important because this is something that happens, it continues to happen. So you may say, well, over a year, but maybe I don't see that much change. But over 10 years, that accumulates. And it accumulates in the loss of function, and ability for walking skills, being able to climb a stair that we see develop in patients with Becker. So we also looked at other functional measures. And this is a bit of a statistical chart, I realize. This is a way of comparing the different functional measures that we looked at. We looked at the timed function tests, 10-meter walk-run, 100-meter timed test, four-stair climb, and rise from floor. And what this shows is a way of comparing them. Even though the North Star is zero to 34, 10 velocities are like 0.2. So you wanna be able to compare, well, which one favored sevasemten? Which one favored placebo? And so the dot tells you the average. The bar tells you the what we call the 95% confidence intervals. We think the true value is somewhere in there based on the relatively small number of patients that we saw. So it went in the right direction for three of the four functional tests. And rise from floor was similar in both, just very close to zero there. So that, again, this is a phase 2 study. It is relatively small numbers of patients, but it's telling us things are moving in the right direction, which is reassuring. Sevasemten was well tolerated. We didn't see any new safety signals. Adverse events are common in people over a year. Lots of things happen. The most common things that we had seen were similar to what we had seen in previous studies. We didn't see any issues in terms of cardiac adverse events, in terms of liver function, kidney function. There was no concern raised there with these additional patients that were on sevasemten for a year. On the next slide. Now, I've talked about. Let me just stay here for a second. I've talked about the adults because they were the primary focus because in the sense that we could design a phase three trial based on natural history. Adolescents, there's very little natural history. In fact, most of the adolescents are right at the top of the North Star scale. The vast majority were over 30. So we don't expect to see very much change there. What we were trying to do really is look at safety and look at the effect on biomarkers. And there, you know, we saw the safety in the adolescents as well. And then we're working through understanding the effect of different dosing levels on biomarkers. So that more to come there. So what are we doing next? Now we are continuing to work on the Grand Canyon study. This is a global study that is conducted at centers across the United States, Europe, Israel, Australia, and New Zealand. This trial was designed to understand whether or not sevasemten had an effect on function. We made it longer, 18 months, to have the study be better powered, better chance of success. One of the advantages of the knowledge that we have from the Canyon study is that we can apply this to analyzing the data in the Grand Canyon study and make sure that we have the right number of patients, make sure that we are analyzing the data in the optimal way to maximize the chance of success. We wanna understand. It is including patients with the same North Star scores, basically the same group of patients. We are aiming to enroll over 120 patients. We are very close to completing enrollment in that study. So that's good because that's moving along and we'll have results in next year for that study as well. We had planned that study to be powered at 90%, which is a good number for if you if, based on what you see that you have statistically a greater than 90% chance of success. We looked at the results that we had in the Canyon study, looked at like things like the variability and how much things changed and were able to say, okay, do we have enough patients in the study? And again, we're well over 90% powered for the Grand Canyon study. So that's encouraging. This is a study again in adults looking at 10 milligrams per day. We are looking at timed function tests, biomarkers of muscle damage, and MRI and patient-reported outcomes. I should touch on MRI, as well. We did include that, in the earlier study. And what we also saw was in Canyon that the treated group, the group that had sevasemten, was somewhat worse at baseline, at the start of the study. And the MRI showed that as well. And that makes it, in general, people who have more advanced disease tend to advance, at least in Duchenne, more rapidly. So although the sample the groups weren't entirely balanced, it was supportive, of the, effect of sevasemten. So I think that's the last. And, we are really excited moving forward to, the Grand Canyon study. And, we really hope to, move things along and make a difference, in the lives of those with Becker. So next, and most of all, we want to thank everybody because this has been an immense effort and it's continuing in Grand Canyon, but it has involved the entire Becker community. We have really been gratified reaching out to the Becker community, as Abby said, listening. And we are most appreciative of the efforts. We know these are young men, adolescents. They have a lot going on, school, jobs, family. And to make time for a clinical trial, which is after all a trial of an investigational agent, we don't know if it's gonna work or not. And we are really enormously appreciative of folks making the time, making the effort to do this. And we have wonderful sites that we are working with across the country, many of which are PPMD centers as well. So thank you. Thank you, PPMD, for supporting. We are very happy to answer questions. And there's we got this data not very long ago. And so we have lots of questions too on the data and understanding it. So there'll be a lot more coming out in the coming months. Thanks so much, Joanne and Abby. Really a very thorough representation of Canyon and Grand Canyon. If you don't mind, I'm gonna take you back and start from slide six. And thank you for teaching us how to say sevasemten. I think we'll get it and I think we'll shorten it to seva for today's discussion. On slide six, this is early on. You know, Abby, you mentioned the community building. And I think those of us who've attended the BEAD, the Becker Education and Engagement Day or BEAD because everything seems to have an acronym. I think those were so incredible for this community to gather. As we know in the Becker community, sometimes it has been very difficult to find fellow patients. And truly, many of them have felt sort of left out because of how diagnosis is made sometimes. And it leaves you sort of without that safety net. So you mentioned BEAD in 2023 and 2024. So I'd like to know what happens in 2025 to BEAD. You're muted, Abby. So yeah, thanks, Pat. BEAD has been probably one of my favorite parts of my jobs right now. It's been so gratifying to see. And BEAD 2025 is gonna happen. We are part of the steering committee. You know, we've identified. I say we, I'm talking about sort of the founders of it. But we are putting together a steering committee. We are gonna probably use some of the same sites again, and we did a survey. We've listened to the feedback from the attendees. How do we make it better? What else do they wanna see? So, the short message though is that yes, we're gonna do it again and we're gonna try to make it bigger and better. Mm-hmm. Great. Thank you. And then on slide eight, we talked about or you talked about the contraction-induced muscle injury, sorry. Can you just explain a little bit about the difference between the Type I, Type II fibers? What are we looking at? Why Type II? You know, is this drug that tries to protect those Type II fibers? Can you tell us a little bit about the difference, so that we understand better? So I'll take a stab at it. And Joanne, do you wanna add in afterwards? I mean, I always think of Type I and Type II fibers as being like your chicken has dark meat and light meat. So, and one type of fiber is more uses oxygen more as energy and one is more glucose-based. And one is used more for, the slower fibers are more, those are the oxygen ones. And they're like the long distance, the endurance athletes. If you're gonna run marathons, you probably have lots of Type I fibers. The Type II fibers are short bursts of power and strength. So why they and Joanne, add anything to that that you want? I do not know why they are the ones that break down first. Yeah. And I think it is because those are a little bit ahead. So if you see that fiber in the lower right-hand corner, and if that one is contracting first, the fast muscle fibers, that's taking the brunt of the whole force across the muscle. And it's like, you know, if you have a rope and you're pulling on a thread in the rope, you can break that easily. And I think many of you probably have seen the mouse video where the contraction induces visible damage, even with a few contractions. So if you modulate that, if you just take even 10% off of that, so it's a little bit slower, then it protects the muscle. And that's what we saw in the animal models. That's what we saw in phase one. And it's continued, too. We look at the biomarkers because if you can protect the muscle, then that should result in longer-term functional benefits because you can't necessarily see those fast. So in our development program, first we're looking at biomarkers and as we move forward, here we are starting to look at functional measures. We couldn't start 120 patients. We didn't know if we had the right dose. And so that's why we did this study initially to make sure we had the right dose in terms of biomarkers and then moved to the larger study that was powered to be able to see a functional test difference. Yeah. Thank you. That's very good. I think sometimes it's really hard to understand Type I and Type II and how they respond in what circumstances. So I really appreciate the explanation. Then if you go to slide 10 and 11, actually, you could probably move to slide 11. We're talking about biomarkers. I think in this community, we've, as a parent, when you receive a diagnosis, whether that's Duchenne or Becker, you receive this very elevated CK. And it is striking. I think we as a community have always leaned on that as some indication of something. So I'm very, you know, that means something knowing that it's incredibly variable across the day or across the population. So can you tell us a little bit about your biomarkers? These are blood biomarkers. You're drawing blood at intervals and looking at averages. Can you tell us, because there are other biomarkers of muscle damage, why you chose TNNI2 and CK? So we chose CK, because it is generally measured. It's something that is available very quickly, in the lab, and is a very easy to measure basically. The fast skeletal muscle troponin, which is different than cardiac troponin or slow muscle, there's two kinds, slow and fast. And what CK comes from all kinds of muscles. So it's not specific to the fast muscle fibers. But TNNI2, fast skeletal muscle troponin, is specific to the fast muscle fibers. So that's why we see a greater relative decrease in that because it's really targeting specifically fast muscle troponin. It's also not in non-dystrophic muscle or it doesn't get released. It is a structural protein in the muscle fiber. And so, I have zero levels of TNNI2. So when we're looking at changes, it's a much more sensitive way of looking at changes rather than CK, which can be elevated in unaffected people. We see this all the time. So it is more specific and we wanna use that. There are other biomarkers that we look at. We look at a whole panel of biomarkers, as well. And we do see changes there as well. That takes longer. We haven't got all of those data yet. But we have seen that in the other studies that this is reflected in other biomarkers of muscle damage, multiple ones. Yeah. Thanks, Joanne. And in any of the studies, did you use a wearable like SV95C to track the changes in the biomarkers to activity as well? Yes. We used a tracker that was not as elegant as the SV95 in the earlier studies. But in Grand Canyon, we are including that. Now, this is exploratory. Nobody has looked at that. But it will be very interesting to see the effect of what the SV95 looks at, how fast people go. It's been very well validated in boys with Duchenne. In fact, the European regulators accept that as a primary endpoint because if they are running faster in everyday life, it's measured over three weeks, then that's a good indication that they have better function. So we are including that. And I think it's exciting to see these digital measures that really reflect what's going on over several weeks, not just over the short time in the clinic. So yeah. I do think the digital measures are really important to see the real world, what happens there and what kind of activity do we see there and what are the changes. So if we move on to the studies themselves and go on to slide 15. Mm-hmm. All right. This is incredibly exciting and you're moving into Grand Canyon. But I would really love for you to just talk a little bit about the DUNE study. I think that all of these studies have different names and they get quite confusing, so could you just elaborate on what is the DUNE study and what are you hoping to achieve there? Yes. The DUNE study was a study that looked at the effect of sevasemten on extreme exercise. Now, when the fast muscle fibers are particularly injured with eccentric contractions, so contracting the muscle and particularly when the muscle is being extended. It's an injury that happens with contraction, contraction-induced injury. That was a study that was conducted in a relatively small number of patients that had an exercise protocol. They came in, they did it exactly the same way. They lifted some weights, they did cycling, and to their near maximum capacity. It was a fairly extreme study. We looked at the biomarkers of muscle function, multiple ones, in the 24 hours after that. We looked at it after everyday life, but we also looked at it after this extreme exercise. What we saw was that with sevasemten, there was a flattening of that increase in biomarkers that you see after extreme exercise. That tells that's corroborating the mechanism of action that this contraction-induced injury is; we protect from it with sevasemten. That's why we did that study. It was at a single site with Dr. Vissing in Denmark. We also looked at a limb girdle and a McArdle disease as well. And we saw decreases in those biomarkers. And I'm gonna jump over to that because I forgot to; I neglected to mention at the end. You know, and people have asked, well, what about Duchenne? We also have, as many of you know, studies ongoing in Duchenne; it's the Lynx study and the Fox study; they're animals. These are stone formations with Becker. What we have been doing is working to try to understand what the best dose is in boys. What we did was we started at a lower dose, much the same way we did back in the early study of Becker. We went up in dose. We looked to see biomarkers for three months and then went up to the next dose. We looked at doses between two and a half and 30 milligrams. What we have seen is that there are decreases in biomarkers. Interestingly, they seem to take longer to happen than in Becker. At least at the lower doses, they take longer to happen than they do in Becker. What we found was that we really need to be in an area between doses of five and 10. That's where people are now who are in the study. We've actually, we're trying now to look on with those doses, what do we see in terms of function? We are using the SV95C there. We see some encouraging results there over longer periods of time in terms of stability. But it's early days really in trying to understand that. So I appreciate it feels it's been a long time for us as well as we've changed doses. But we are looking to share more data on that in the new year. So just to nail down new year because we're all anxious for news there. You think it'll be first quarter new year where you'll be able to talk about Duchenne? There'll be some. But when we focused on these doses, we need some time with these doses to understand that. So there'll be more kind of second quarter of next year. Yes. Thanks, Joanne. So while we're on dosing, can you go to the next slide, the slide 16? And this is where we see doses for your Canyon. So we're back to the Becker Canyon study. And 10 milligrams for the adults is apparently where you've landed for Grand Canyon. And then, I noticed in Grand Canyon, you're not including the adolescent population. Is that because the dose question is still uncertain or is there some other reason? Yes. We wanted to see these doses and what effects we had on biomarkers, what levels we saw in the bloodstream before that. We are anticipating that we will move into a study with more adolescents in the new year. So be a separate study than Grand Canyon. Is that correct? And while we're talking about studies, what are your plans for studies in a non-ambulatory population of Becker? That's a good question. Now, one of the reasons is that we were able to identify a group of patients where we could potentially see changes in North Star is because of the natural history data that's come out over the last 10 years, 8 to 10 years, that show that this group of patients has. We have an understanding of how the disease progresses, how we can measure that. And for non-ambulatory patients, one of the things is arm function with the PUL, where we included that actually in the Canyon and the Grand Canyon study, because people do develop limitations in terms of upper limb function or arm function. What we have been trying to sort out is also whether we do a non-ambulatory study to look at safety and PK because again, we're not going to be able to really understand there isn't enough information to design a study to be able to look at functional changes in the non-ambulatory population. I think that the PUL 2.0 is certainly a good way to evaluate. I'm also wondering, Joanne, if you have done any cardiac testing across these studies, both Duchenne and Becker through all the Canyon, et cetera studies. Are you looking at the heart and seeing and understanding what benefit or stability might be present? Yes. We are, so sevasemten does not interact with cardiac muscle. It's a different myosin. So we don't expect that it would have any direct effect on the heart in terms of its function. We measured. We looked with echo every six months during this study. And compared with placebo, there's no change in the sevasemten group. So we're not seeing any effects in terms of or certainly we're not seeing any negative effects there. This is across all studies. Is that right? Well, this is across this study and yes. So in Canyon because that's the placebo-controlled one we have. Right. Okay. And then if we could go to slide 20. Uh-huh. First of all, decreasing the biomarkers is really incredible. And I think something that is really near and dear to all of our hearts. I think that I wonder just your opinion and perhaps this is, in Duchenne, are you measuring the same and anticipating similar results in terms of change in biomarkers? We are measuring these biomarkers in Duchenne, yes. So, and that we are looking to see if, you know, at similar blood levels, we're seeing the same. It is a little different in Duchenne that it does take longer to see. So that would because it takes longer to see, do you envision a study in Duchenne that might have to be longer than 12 months, extending on to an 18-month study? That's a good question. And I don't think we have enough information to answer that. But I would say that we see that we've heard with other investigational agents that maybe 12 months isn't enough, which I know people don't want to hear because nobody wants to be on placebo for 18 months, and it's how do we figure out how to make these trials as successful as possible. But it may take longer. Yes. Yeah. I worry about that. I also worry, you know, in your Becker study and your Canyon and Grand Canyon and all of the other associated studies, those patients were largely steroid naive. And now you've got a Duchenne population that is not. And if I am understanding correctly what's out there, there are so many and many and varied doses and regimens in terms of steroids. Now with the Agamree as a new approval, how are you thinking about a Duchenne study with that variability? Do you expect that the steroid uncertainty in terms of dose and regimen, start time, et cetera, will potentially be a confounder as you move forward in Duchenne? It's a very complex landscape out there, certainly. Not only that, but other therapies, and how do we stratify for that? We do not at this point have a, you know, that's what we're looking at these data for to be able to better design the study. To how do we stratify? How do we make sure that the groups are balanced with respect to baseline steroids and other treatments is something that we're going to have to take into consideration. Yeah. I I think that's a hard one. I think you had a slide, I think it was 21 or 22 on the natural history, and you talked about stability, right? Yeah. Good. Thank you. I just FYI, we are really engaged in a study on a preference study to look at stability because I think in all of these diseases, if you could achieve stability, I mean, we are all looking for benefit. But benefit is stability, right? If you can remain stable for years and years, I think there's not anyone who goes to bed at night and doesn't pray to whoever they pray to just stop it here. So I'm hopeful for stability and I'm hopeful EMA will recognize the stability because as you mentioned, loss of one point on the North Star, 1.8 over a period of a year means a significant change. I really think I understand the rise from floor. That's a hard one because those core muscles are so dependent on the rise from floor where the other muscles are sometimes grouped in terms of ability. So I applaud you for the trends that I'm seeing here. In the Grand Canyon, we talked about the fact, and this is slide 24, so we'll move to that one. You're at 90%. Tell us when you think that'll be fully recruited. I guess in all of that, Joanne, as you get fully recruited, are you considering talking to FDA or regulatory authorities in the U.S., and accelerated approval pathway for based on your biomarkers? When you fully enroll, is that sort of a plan to go forward? Mm-hmm. We got the data last week. We are putting together a package. We certainly will go to the FDA with this information and talk about the approval pathway going forward, both the FDA as well as European regulators, to understand going forward. We don't know the answer to that question. Yes, we have fast track to allow us to have more interactions with them and understand. It'll be a big. It's important for them to understand in this rare disease without other treatments, you know, how can we move forward as quickly as possible, as everybody wants to. Yeah. Thank you for that, Joanne. We certainly wish you luck on accelerated approval. Are you applying to Canada and, in addition to the FDA, the EMA, are you looking at other countries like Canada or Asia or other regulatory agencies? Are you thinking broadly? Yes, we are. We haven't laid it all out yet. I mean, our assumption is that we would go with the Grand Canyon. If we can go faster, that would be great. But Grand Canyon, we anticipate right now we are almost fully enrolled in the study. And so we expect that we will share that we're fully enrolled first quarter of next year. That's wonderful. Certainly as a community, we applaud your efforts in Duchenne as well. Obviously protecting those Type II fibers in Duchenne, even though it may take longer to see, is really amazing. And I also applaud you for doing the Lynx study because I think people who've been in a gene therapy protocol or received the currently approved Elevidys are certainly looking toward the future and saying, how do we get to combination? So I really am very thankful for your interest in moving into that space as well. So this is maybe a crazy question, Joanne. And you're allowed to say it's a crazy question. But so for example, let's say the data continues to look good. You're submitting a package to the FDA in our case, and other regulators, EMA and Canadian, et cetera. And you're going, at least in the U.S., excuse me, on the accelerated approval pathway. And let's say with all things going forward, within that submission, the FDA does, excuse me, grant an approval for Becker. What is to prevent a physician from two things. One is, could that provide you an easier pathway for an expanded label in Duchenne, a modified study that could get you an approval? And two, if I was taking my son to my clinic and you were approved in Becker, would there be any chance of getting access as an off-label prescription? So, let me back up one point that when I say package, what I mean is that we're going to present them with, here's what we have today. We want to sit down and talk. We're not saying I don't want package to be interpreted as submitting an NDA with this information. First thing is to talk to them and understand that they like that. They want to be able to ask us questions and. They like to get the scoop. That's for sure. Exactly, and as I said, also the open-label extensions are important parts of that, and in terms of the way that the system works in the United States is that there is this thing called off-label use that physicians can do. It's also complicated by their payers. But I think fundamentally we need to understand how the drug would be dosed in boys first. And I'm confident that physicians would want to understand that and have the data in hand to broaden, to be able to broaden the label. But that is, you know, the steps is if we got approval, then we would potentially broaden the label into Duchenne. Thank you. You know, we're all anxious to get the combination therapies, Joanne. So we're going to try to do whatever we can to help you accelerate the understanding. And in the adolescent group, you mentioned in previous slides the adolescent group of Canyon. I think the dose level was up to 12.5 mg from 5 milligrams to 12.5, if I remember correctly. Have you landed on a dose in those adolescents? We are working with our PK folks are analyzing that and looking at biomarker responses. So that is on the docket. You have a lot of questions. We have a lot of questions in terms of trying to understand the data better, and making the right decisions going forward. Well, thank you. Last question, can we expect in Duchenne an expanded study in the near future, based on the fact that you are learning about dosing? You have the two studies underway. You'll. I'm suspecting you have open label extensions on those studies. And then will there be a phase three in Duchenne in 2025? Yeah. So that's what we are planning to understand the data in Fox and Lynx and to be able to outline what our plans are for a phase three study later in the year. That's our goal. Good. So we can maybe have a follow-on webinar with additional data, fully recruited Canyon and Grand Canyon study, additional data on Duchenne and maybe some of the scoop that you've had from the FDA. Well, I can't thank you enough for this. We're very excited about this. Excited about what you're doing. Excited about using. I think you are the first company that's used the CK and the TNNI2 as biomarkers and CK as a primary. I think as a community, we've always wished and I remember Janet Woodcock in 2016 said, "CK is a good biomarker. You just have to understand it a bit better." So I think this is great progress. And I can't thank you enough for what you're doing. Thank you from our community. Thank you for doing the whole Becker and bringing that whole community together. They deserve nothing less. So we're really behind you in that and thrilled about your work in Duchenne. So with that, I will answer the question that this webinar has been recorded and it will be posted very shortly after today, and you might have to give us a day or so and it will be posted. We thank you both for joining us, Abby and Joanne. And we wish you all the best for the holidays, but all the best selfishly for our community as well. Thank you for joining us today. Thank you so much. All the best for a nice holiday. Yeah.